Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) plays a crucial role in intracellular calcium signaling, influencing neuronal health and pathology. While NAADP is essential for synaptic signaling and neuronal survival, it can also contribute to neurodegeneration during inflammatory responses, particularly in conditions of excitotoxic glutamate stimulation. This project aims to elucidate the mechanisms by which NAADP-binding proteins HN1L/JPT2 and LSM12 modulate calcium signaling and neurodegeneration. Under homeostatic conditions, NAADP signaling promotes protective calcium dynamics, while during neuroinflammation it may promote excessive calcium influx and neurotoxicity. We will employ mouse models with neuron-specific deletions of HN1L/JPT2 and LSM12, to investigate the intracellular calcium handling utilizing methodologies such as calcium imaging and real-time assays of neuronal viability. Thereby we will identify the nature of global and local calcium signals in neurons subjected to glutamate stimulation and evaluate the role of NAADP in lysosomal exocytosis and its neurotoxic effects. The assessment of these pathways in an experimental autoimmune encephalomyelitis (EAE) model of neuroinflammation.
We anticipate that our findings will clarify the distinct roles of NAADP-binding proteins in calcium signaling and their contributions to neuronal excitotoxicity. This research may identify novel therapeutic targets for mitigating neurodegeneration associated with excitotoxicity and inflammatory conditions, ultimately advancing our understanding of NAADP signaling in neuronal health and disease.
Teilprojekt zu: FOR NeuroFlame – Defence and demise of inflamed neurons.
Teilprojektleiter: Professor Dr. Marc Freichel; Professor Dr. Andreas Guse